Case 14 – summary

The idea behind this case was to look at a relatively common problem, prolonged APTT and recognise how we should be acting upon it.

There are a number of causes of a prolonged APTT.  In this case the best approach was to repeat the test initially.  Obviously the bleeding history makes further testing more relevant, and relatively urgent.

Causes of an isolated prolonged APTT:

• Deficiencies of either XII, XI, IX & VIII. However, the APTT can be normal with mild deficiencies of these clotting factors. In general the deficient factor has to be less than 20-40% of normal before the APTT is prolonged
• Contact factor deficiency e.g. pre-kallikrein deficiency
• Acquired clotting factor inhibitors – these are most commonly directed against FVIII and may occur as either autoantibodies [e.g. acquired Haemophilia A] or alloantibodies (in individuals with severe Haemophilia A following exposure to exogenous factor VIII e.g. the use of factor VIII concentrate to treat a bleed). Inhibitors against other clotting factors are rare but do occur e.g. Factor V

.

• Lupus anticoagulant [LA] – a LA targets phospholipid and so can result in an isolated prolongation of the APTT. Although the PT requires phospholipid the concentration of PL in the PT reagents is high and so it frequently neutralises the LA and so the PT is not prolonged.

Presence of lupus anticoagulant, or acquired clotting inhibitors would prevent correction of the APTT  mixing studies (patient plasma is mixed with normal plasma [ratio 1:1])  Therefore in this case we suspected a factor deficiency, which was confirmed by lower factor VIII levels, also prompting a von willibrands screen.

Obviously this patient gave no history of von-willibrands disease prior to this admission, but had noted some recent bleeding.  The fact that he had no previous history should not deter from completing a full screen, as in this case he had acquired von willibrands disease.

The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF).

VWF abnormalities in these disorders can result from

(1) antibody-mediated clearance or functional interference

(2) adsorption to surfaces of transformed cells or platelets

(3) increased shear stress and subsequent proteolysis.

AVWS is usually associated with an underlying disorder. According to the ISTH registry, lymphoproliferative (48%), cardiovascular (21%), myeloproliferative (15%), other neoplastic (5%), and autoimmune disorders (2%) are most frequent.¹⁶ Less commonly, AVWS has been described in hypothyroidism, uremia, or without an underlying disorder.

There are 2 main scenarios in which the diagnosis of AVWS should be considered: (1) bleeding patients in whom laboratory testing suggests abnormalities of VWF and (2) patients with known AVWS-associated disorders seeking advice before undergoing procedures associated with a high risk of bleeding

When completing a von-willibrands screen the

• VWF-Ag is reduced
• VWF-RCO/Ag ratio is normal (or reduced with HMW multimers reduced or absent)

The initial tests used to assess AVWS are the same as for von Willebrand disease.

Differentiating von willibrands disease from acquired von willibrands syndrome:

Aspect	In favor of AVWS	In favor of VWD	Limitations
Personal history	Late onset of bleeding Uneventful surgery before onset of bleeding	Early onset of bleeding No uneventful surgery or no previous high-risk situations	Variable penetrance of VWD
Family history	Negative	Positive	Variable penetrance of VWD
AVWS-associated disorder	Present	Absent	Coincidental presence of highly prevalent disorders (eg, MGUS in the elderly)
Laboratory evaluation	Presence of inhibitor or VWF-binding antibodies	VWF gene mutation	Low frequency of detectable inhibitors in AVWS Alloantibodies in rare cases of VWD type 3
Treatment response	Remission after treatment of underlying disorder Response to IVIG (in IgG-MGUS-associated AVWS) Short-lived response to VWF-containing concentrates or desmopressin	Normal recovery and half-life of VWF-containing concentrate Sustained response to desmopressin	Cannot be assessed before treatment

Theurapeutic options depending upon underlying disease

Underlying disorder	Causal treatment	Additional treatment options
Autoimmune disorders
Systemic lupus erythematosus	Steroids, cyclophosphamide	IVIG (only IgG-MGUS or anti-VWF IgG), plasmapheresis, antifibrinolytics, VWF-containing concentrate, rFVIIa
Lymphoproliferative disorders
MGUS	Usually untreated
Lymphoma, multiple myeloma	Chemotherapy according to entity
Cardiovascular
Aortic valve stenosis and other anomalies with increased shear stress	Corrective surgery	VWF-containing concentrate, antifibrinolytics
Dysfunctional heart valve prosthesis, LVAD	Corrective surgery if applicable	Reduce or withdraw anticoagulation, VWF-containing concentrate
Myeloproliferative neoplasia
Essential thrombocythemia	Cytoreductive therapy, chemotherapy, or stem cell transplantation in case of progression
Polycythemia vera	Phlebotomy, cytoreductive therapy, chemotherapy, or stem cell transplantation in case of progression	Withdraw aspirin (if applicable), desmopressin, antifibrinolytics, VWF-containing concentrate
Chronic myeloid leukemia	Tyrosine kinase inhibitors, stem cell transplantation

Treatment options for an acute bleed:

• Desmopressin
• VWF concentrates
• IVIG
• Antifibrinolytics

Causes of isolated low factors VIII levels:

1. Haemophilia/acquired haemophilia
2. Von-willibrands
3. Blood group O (can be clinically significant)

Note:

A normal aPTT does not exclude mild factor VIII deficiency, because the aPTT may not be sufficiently sensitive to detect slightly reduced levels of factor VIII-C in the approximate 20-30% range needed.  Often in acquired von-willibrands disease the APTT can be normal, but the new onset of bleeding should prompt further investigation.

Further reading

http://bloodjournal.hematologylibrary.org/content/97/7/1915.long

How I treat patients with von Willebrand disease Blood Journal  April 1, 2001 vol. 97 no. 7 1915-1919